The combined use of B vitamins and probiotics promotes B vitamin absorption and increases Akkermansia abundance.

B vitamins and probiotics are commonly used dietary supplements with well-documented health benefits. However, their potential interactions remain poorly understood. This study aims to explore the effects and underlying mechanisms of the combined use of B vitamins and probiotics by liquid chromatography-triple quadrupole mass spectrometry analysis, pharmacokinetic modeling, and 16S rRNA gene sequencing. By intragastric administration of seven B vitamins and three Lactobacillus strains to healthy rats (n = 8 per group), we found that probiotics significantly promoted the absorption (by approximately 14.5% to 71.2%) of vitamins B1, B3, B5, and B12. By conducting in vitro experiments (n = 3 per group) and a pseudo-germ-free rat model-based pharmacokinetic study (n = 6 per group), we confirmed that probiotics primarily enhanced the B vitamin absorption through gut microbiota-mediated mechanisms, rather than by directly producing B vitamins. Furthermore, we evaluated the effects of B vitamins and probiotics on the colon and gut microbiota by treating the pseudo-germ-free rats with blank solution, B vitamins, probiotics, and B vitamins + probiotics (n = 5 per group), respectively. Histopathological examination showed that the combination of B vitamins and probiotics synergistically alleviated the rat colon damage. High-throughput genetic sequencing also revealed the synergistic effect of B vitamins and probiotics in modulating the gut microbiota, particularly increasing the abundance of Verrucomicrobia and Akkermansia. In summary, the combined administration of B vitamins and probiotics may have a higher efficacy than using them alone.

An In Silico Platform to Predict Cardiotoxicity Risk of Anti-tumor Drug Combination with hiPSC-CMs Based In Vitro Study.

OBJECTIVE: Antineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body's regulatory response to cardiomyocyte injury. METHODS: Here, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction. RESULTS: A total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31-2.7% for single-agent treatment and 0.15-10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50-1.0% and 1.5-8.3%, respectively). CONCLUSIONS: In conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents.

Intermediate role of gut microbiota in vitamin B nutrition and its influences on human health.

Vitamin B consists of a group of water-soluble micronutrients that are mainly derived from the daily diet. They serve as cofactors, mediating multiple metabolic pathways in humans. As an integrated part of human health, gut microbiota could produce, consume, and even compete for vitamin B with the host. The interplay between gut microbiota and the host might be a crucial factor affecting the absorbing processes of vitamin B. On the other hand, vitamin B supplementation or deficiency might impact the growth of specific bacteria, resulting in changes in the composition and function of gut microbiota. Together, the interplay between vitamin B and gut microbiota might systemically contribute to human health. In this review, we summarized the interactions between vitamin B and gut microbiota and tried to reveal the underlying mechanism so that we can have a better understanding of its role in human health.

A quantitative systems pharmacology approach to predict the safe-equivalent dose of doxorubicin in patients with cardiovascular comorbidity.

Patients with cardiovascular comorbidity are less tolerant to cardiotoxic drugs and should be treated with reduced doses to prevent cardiotoxicity. However, the safe-equivalent dose of antitumor drugs in patients with cardiovascular disease/risk is difficult to predict because they are usually excluded from clinical trials as a result of ethical considerations. In this study, a translational quantitative system pharmacology-pharmacokinetic-pharmacodynamic (QSP-PK-PD) model was developed based on preclinical study to predict the safe-equivalence dose of doxorubicin in patients with or without cardiovascular disease. Virtual clinical trials were conducted to validate the translational QSP-PK-PD model. The model replicated several experimental and clinical observations: the left ventricular ejection fraction (LVEF) was reduced and the left ventricular end-diastolic volume (LVEDV) was elevated in systolic dysfunction rats, the LVEF was preserved and LVEDV reduced in diastolic dysfunction rats, and patients with preexisting cardiovascular disease were more vulnerable to doxorubicin-induced cardiac dysfunction than cardiovascular healthy patients. A parameter sensitivity analysis showed that doxorubicin-induced cardiovascular dysfunction was mainly determined by the sensitivity of cardiomyocytes to cardiotoxic drugs and the baseline value of LVEDV, reflected in LVEF change percentage from the baseline. Blood pressure was the least sensitive factor affecting doxorubicin-induced cardiotoxicity.

The Combination of Cell Cultured Technology and In Silico Model to Inform the Drug Development.

Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

Therapeutic Duration and Extent Affect the Effect of Moxibustion on Depression-Like Behaviour in Rats via Regulating the Brain Tryptophan Transport and Metabolism.

Moxibustion has been widely accepted as an alternative therapy for major depressive disease (MDD). However, the efficacy of moxibustion treatment on MDD is highly variable because of its irregular operation. This study was designed to investigate how therapeutic duration and extent influence the anti-depression effect of moxibustion and the underlying mechanism involved. Rats with lipopolysaccharide-induced depression-like behavior were treated by moxibustion treatment. The anti-depression effect was determined by forced swimming test and open field test. Tryptophan (Trp) transport and its metabolism to serotonin (5-HT) and kynurenine (Kyn) were evaluated to explore the anti-depression mechanism. The results showed that moxibustion treatment could alleviate the depression-like behavior in rats. Trp transport and 5-HT generation were significantly increased, and the Trp-Kyn pathway was moderately inhibited by moxibustion. Prolonged therapy could be beneficial to the anti-depression effect by promoting the brain uptake of Trp and shifting the Trp metabolism to 5-HT. An enhanced therapeutic extent could increase 5-HT generation. In conclusion, this study determined that the anti-depression effect of moxibustion involves improved Trp transport and metabolism. The therapeutic duration benefits antidepressant effects, but the complex influence of the therapeutic extent on moxibustion efficacy requires further studies.

Zinc-mediated α-regioselective Barbier-type cinnamylation reactions of aldehydes, ketones and esters.

We report a simple, efficient, and general method for the zinc-mediated regioselective cinnamylation of aldehydes and ketones under Barbier-type conditions in a one-pot synthesis affording the corresponding α-cinnamylated alcohols in moderate to excellent yields. Compared to the literature procedures, this approach is operationally simple, uses simple reactants, and provides direct access to linear α-cinnamylated alcohols with excellent regioselectivity. Experimental results suggest that the reactions proceed through the radical pathway. In addition, the reaction was found to be scalable to the gram-scale and the one-pot protocol is also applicable to less reactive esters leading to bishomoallylic alcohols which were valuable intermediates for desymmetrizing intramolecular Heck cyclization, allowing for the elaboration to functionalized building blocks.

Preparation and properties of a novel macro porous Ni2+-imprinted chitosan foam adsorbents for adsorption of nickel ions from aqueous solution.

In this study, novel macro porous Ni2+-imprinted chitosan foam adsorbents (F-IIP) were prepared using sodium bicarbonate and glycerine to obtain a porogen for adsorbing nickel ions from aqueous solutions. The use of the ion-imprinting technique for adsorbents preparation improved the nickel ion selectivity and adsorption capacity. We characterised the imprinted porous foam adsorbents in terms of the effects of the initial pH value, initial metal ion concentration, and contact time on the adsorption of nickel ions. The adsorption process was described best by Langmuir monolayer adsorption models, and the maximum adsorption capacity calculated from the Langmuir equation was 69.93mgg-1. The kinetic data could be fitted to a pseudo-second-order equation. Our analysis of selective adsorption demonstrated the excellent preference of the F-IIP foams for nickel ions compared with other coexisting metal ions. Furthermore, tests over five cycle runs suggested that the F-IIP foam adsorbents had good durability and efficiency.

Comparison of Co(2+) adsorption by chitosan and its triethylene-tetramine derivative: Performance and mechanism.

A cross-linked chitosan derivative (CCTS) was synthesized via cross-linking of epichlorohydrin and grafting of triethylene-tetramine. The adsorption performance and capacity of the raw chitosan (CTS) and its derivative were also investigated for removal of Co(2+) from aqueous solution. A maximum adsorbed amount of 30.45 and 59.51mg/g was obtained for CTS and CCTS, respectively under the optimized conditions. In addition, the adsorption kinetics for the adsorption of Co(2+) by CTS and CCTS were better described by the pseudo second-order equation. The adsorption isotherm of CCTS was well fitted by the Langmuir equation, but the data of the adsorption of Co(2+) onto CTS followed Freundlich and Sips isotherms better. Furthermore, the adsorbent still exhibited good adsorption performance after five regeneration cycles. Finally, Co(2+) removal mechanisms, including physical, chemical, and electrostatic adsorption, were discussed based on microstructure analysis and adsorption kinetics and isotherms. Chemical adsorption was the main adsorption method among these mechanisms.

Stencil mask methodology for the parallelized production of microscale mechanical test samples.

A new methodology to parallelize the production of micromechanical test samples from bulk materials is reported. This methodology has been developed to produce samples with typical gage dimensions on the order of 20-200 µm, and also to minimize the reliance on conventional focused ion beam fabrication methods. The fabrication technique uses standard microelectronic process methods such as photolithography and deep-reactive ion etching to create high aspect ratio patterned templates-stencil masks-from a silicon wafer. In the present work, the stencil mask pattern consists of a linear row of tensile samples, where one grip of each sample is integrally attached to the bulk substrate. Once fabricated, the stencil mask is placed on top of a pre-thinned substrate, and the pattern and substrate are co-sputtered using a broad ion beam milling system, which ultimately results in the transfer of the mask pattern into the substrate. The methodology is demonstrated using a Si stencil mask and a polycrystalline Ni foil to manufacture an array of metallic micro-tensile samples.

Simultaneous absorption of NOx and SO2 from flue gas with pyrolusite slurry combined with gas-phase oxidation of NO using ozone.

NO was oxidized into NO(2) first by injecting ozone into flue gas stream, and then NO(2) was absorbed from flue gas simultaneously with SO(2) by pyrolusite slurry. Reaction mechanism and products during the absorption process were discussed in the followings. Effects of concentrations of injected ozone, inlet NO, pyrolusite and reaction temperature on NO(x)/SO(2) removal efficiency and Mn extraction rate were also investigated. The results showed that ozone could oxidize NO to NO(2) with selectivity and high efficiency, furthermore, MnO(2) in pyrolusite slurry could oxidize SO(2) and NO(2) into MnSO(4) and Mn(NO(3))(2) in liquid phase, respectively. Temperature and concentrations of injected ozone and inlet NO had little impact on both SO(2) removal efficiency and Mn extraction rate. Specifically, Mn extraction rate remained steady at around 85% when SO(2) removal efficiency dropped to 90%. NO(x) removal efficiency increased with the increasing of ozone concentration, inlet NO concentration and pyrolusite concentration, however, it remained stable when reaction temperature increased from 20°C to 40°C and decreased when the flue gas temperature exceeded 40°C. NO(x) removal efficiency reached 82% when inlet NO at 750 ppm, injected ozone at 900 ppm, concentration of pyrolusite at 500 g/L and temperature at 25°C.